|Genetic Finding Suggests Alternative Treatment Strategy for
Common, Complex Skin Disorders and Asthma
Ineffective Skin Barrier May Trigger Immune Reaction, Illness
A genetic finding by researchers at the National Institutes of Health provides
new insight into the cause of a series of related, common and complex illnesses – including
hay fever and asthma as well as the skin disorders eczema and psoriasis – and
suggests a novel therapeutic approach. These illnesses are essentially inflammatory
disorders of the tissues that separate the inside of the body from the outside
world, such as the skin and the linings of the throat and lungs.
In the May issue of The Journal of Clinical Investigation, researchers
from the National Human Genome Research Institute, the National Eye Institute,
and the National Institute of Child Health and Human Development, all part of
the National Institutes of Health, report that excessive production of a specific
protein disrupts the protective properties of the skin barrier. Once the skin
barrier is compromised, immune-system-stimulating chemicals — allergens — can
enter the body and cause an inflammatory reaction that, in turn, stimulates skin
cells to grow rapidly, further diminishing the protective function of the skin.
The compromised barrier, in turn, becomes more porous to allergens that then
stimulate more inflammation in a cycle that eventually produces common skin conditions
such as psoriasis and eczema.
It may, however, be possible to break the cycle by creating a temporary, artificial
barrier on the skin that blocks incoming allergens. The solution could be as
simple as developing a lotion that effectively blocks allergens from getting
through damaged skin. Keeping allergens out of the skin would keep the immune
system from over-stimulating cell growth, giving the skin time to re-create a
normal barrier. Current therapies for these skin conditions principally focus
on suppressing the immune system, but the medicines used can produce undesired
“The human body is an incredibly complex system,” said Elias A. Zerhouni, M.D.,
director of the National Institutes of Health. “Only by conducting this kind
of basic research can we hope to understand the causes of complex diseases. And
only by understanding disease can we produce a future in which we can predict
who is at risk, pre-empt the illness from ever occurring and personalize the
treatment when it does.”
Several recent studies have suggested that defects in the skin barrier may be
as important to eczema and psoriasis as the hyperactive response of the immune
system. In addition, doctors have observed that individuals with eczema are also
likely to develop hay fever and asthma, suggesting a common mechanism for both
disorders. The other risk factor for these conditions is having a relative with
the disorder, suggesting a genetic connection.
To test whether a defective skin barrier can actually produce these diseases,
a team of NIH researchers focused on a specific gene called connexin 26, which
makes a protein that forms connections between skin cells that create the normal
barrier. When the skin is intact, the production of connexin 26 is turned off
once there is enough to hook all the skin cells together. When skin is damaged
by a cut or a scrape, connexin 26 is produced while new skin cells reproduce
and heal the wound. Researchers have shown that connexin 26 production is turned
on in the sore skin of people with psoriasis, but it wasn’t clear what role connexin
26 played in the disorder.
To determine connexin 26’s role in psoriasis, NIH researchers created a line
of transgenic mice that over-produce connexin 26. The resulting mice develop
psoriatic-type skin sores, just like humans with psoriasis.
“This discovery demonstrates the power of animal models to unravel complex conditions
of medical importance,” said Eric D. Green, M.D., Ph.D., NHGRI’s scientific director
and the director of the institute’s Division of Intramural Research, where the
research was conducted. “Our current abilities to rapidly create new genetically
altered animal models allow researchers to move from conception of an idea to
its implementation at an incredible pace.”
The discovery broadens the basic understanding of the causes of skin disorders
such as psoriasis and eczema, and may well contribute to the basic understanding
of asthma and hay fever, conditions that arise when allergens penetrate the tissue
barrier in the lungs and nose, respectively.
“Hopefully, this will help us understand the complex genetics of psoriasis,” said
Julia A. Segre, Ph.D., an investigator in NHGRI’s Genetics and Molecular Biology
Branch and the senior author on the paper. “Previous genetic studies have focused
on the genes that regulate immune response. We are now examining the effect of
genes that are involved in both regulating the growth of skin cells and signaling
to the immune cells.”
The problem causing these related disorders may simply be the body over-reacting
to an allergen getting through the barrier that is supposed to block it. “The
skin goes into a stress response and overcompensates by trying to rebuild the
barrier too fast, actually becoming less effective,” Dr. Segre said. “The skin
cells grow so fast that they fail to make a normal barrier, and the body is stimulating
the immune response because of material (chemicals and allergens) coming through
Understanding the genetics of skin disorders may well have important
implications for other serious illnesses, such as asthma. It
is not uncommon for a family doctor
to face the dilemma of a child who has eczema and then having to
decide how aggressively to treat the disease. Eczema is not particularly
dangerous, but children presenting
with eczema commonly go on to develop asthma, which severely compromises
quality of life and in rare cases can be lethal. Treating eczema
drugs, which may also prevent asthma from developing, may cause
undesirable side effects.
The genetic studies suggest that researchers now need to focus on both turning
down the immune response, as well as restoring a normal skin barrier to keep
the outside world out of the body.
“The barrier function of epithelial surfaces is important in all tissues that
have contact with the outside world. In addition to the skin and respiratory
tract, it includes the gastrointestinal tract, and the ocular surface,” said
Ali Djalilian, M.D., formerly a research fellow and medical officer at the National
Eye Institute but now at the University of Illinois in Chicago, and the lead
author of the paper. “These findings underline the importance of this barrier
function and suggests a new strategy for restoring it in human diseases.”
Among the most serious, common chronic conditions in the United States, asthma
affects more than 20 million people. Some 5 million asthmatics are U.S. children
younger than 18 and approximately 3.6 million children have had an asthma attack
within the last year. Nearly half a million attacks resulted in a trip to the
emergency room each year and more than 5,000 asthmatics died from their illness.
More information about asthma can be found at http://www.nlm.nih.gov/medlineplus/asthma.html.
An estimated 4.5 million U.S. adults suffer from psoriasis, up to a third suffer
with a moderate to severe form of the disorder, including 1 million who have
psoriatic arthritis. More information about psoriasis can be found at http://www.nlm.nih.gov/medlineplus/psoriasis.html.
More than 15 million Americans suffer from the symptoms of eczema, according
to the National Institute of Arthritis and Musculoskeletal and Skin Diseases,
a part of the National Institutes of Health. More information about eczema can
be found at http://www.nlm.nih.gov/medlineplus/eczema.html.
Approximately 50 million Americans suffer some form of allergy or hay fever,
experiencing sneezing, runny nose or watery eyes, though the symptoms can range
from mild to life-threatening. More information can be found at http://www.nlm.nih.gov/medlineplus/allergy.html.
The National Human Genome Research Institute, the National Eye Institute
and the National Institute of Child Health and Human Development are among
the 27 institutes and centers that make up the National Institutes of Health
(NIH) — The Nation's Medical Research Agency.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.